Suppressive effect of dexamethasone on TIMP-1 production involves murine osteoblastic MC3T3-E1 cell apoptosis

Institute of Endocrinology and Metabolism, Second Xiangya Hospital of Central South University, 139 Middle Renmin Road, Changsha, Hunan, 410011, People's Republic of China.
Amino Acids (Impact Factor: 3.29). 08/2009; 38(4):1145-53. DOI: 10.1007/s00726-009-0325-9
Source: PubMed


High dose glucocorticoid (GC) treatment induces osteoporosis partly via increasing osteoblast apoptosis. However, the mechanism of GC-induced apoptosis has not been fully elucidated. Osteoblast-derived tissue inhibitor of metalloproteinase-1 (TIMP-1) was recently reported to be involved in bone metabolism. Our previous study demonstrated that TIMP-1 suppressed apoptosis of the mouse bone marrow stromal cell line MBA-1 (pre-osteoblast) induced by serum deprivation. Therefore, we tested the effect of the GC dexamethasone (Dex) on TIMP-1 production in murine osteoblastic MC3T3-E1 cells and further determined whether this action is associated with Dex-induced osteoblast apoptosis. Dex decreased TIMP-1 production in MC3T3-E1 cells, and this effect was blocked by the glucocorticoid receptor (GR) antagonists, RU486 and RU40555. Recombinant TIMP-1 protein reduced caspase-3 activation and apoptosis induced by Dex in MC3T3-E1 cells. In addition, the pro-apoptotic effect of the Dex was augmented by suppression of TIMP-1 with siRNA. Furthermore, mutant TIMP-1, which has no inhibitory effects on MMPs, yet protects MC3T3-E1 cells against Dex-induced apoptosis. Our study demonstrates that Dex suppresses TIMP-1 production in osteoblasts through GR, and this effect is associated with its induction of osteoblast apoptosis. The anti-apoptotic action of TIMP-1 is independent of its inhibitory effects on MMPs activities. The decrease in TIMP-1 production caused by Dex may contribute to the mechanisms of Dex-induced bone loss.

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    • "The effects of GCs are primarily considered to be mediated by cytosolic glucocorticoid receptor (GR) activation [5], but the events leading from the activated GR to growth arrest are not yet elucidated completely. Previous studies have reported that GCs treatment induce osteoblast apoptosis by enhancing the expression of BH3-only protein Bim [6], down-regulation of TIMP-1 [7], and activation of glycogen synthase kinase 3 beta (GSK-3β) [8]. But to the best of our knowledge, there is no direct relationship between GR and these proteins, such as transcription-control or protein-protein interaction. "
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